The overall goals of this line of research are to develop innovative methods to treat cigarette smokers, and to understand the processes related to smoking and relapse. The proposed research is based upon a chronic disorder model of cigarette smoking that suggests that long-term treatment targeted at relapse precipitants may be useful. Based on this model, we have developed a relapse prevention treatment that uses a cognitive-behavioral framework to intervene on five areas important in relapse prevention, according to the 2000 Practice Guidelines. These areas are fluctuating motivation, depression, withdrawal, weight gain, and social support. [Data] from this line of research and [preliminary data from a] related line of research (Maintaining Abstinence in Chronic Cigarette Smokers, R01 DA015732) suggest that this targeted relapse prevention treatment provided over a one year period can produce CO-verified abstinence rates of [over 50%]. These high rates are maintained at a two year follow-up. It is important to extend these findings from a smoking research clinic to a health care setting, using recruiting procedures, personnel, and patient populations prototypical of health care settings. There is also a need to extend them to smokers with a range of medical and psychiatric disorders. Last, it will be useful to establish the effects of the targeted relapse prevention intervention on abstinence over and above those obtained with extended nonspecific supportive treatment [based on a Health Education model]. Thus, the proposed research will test a series of hypotheses about the efficacy of targeted relapse prevention treatment in relation to extended nonspecific treatment and brief treatment. Participants (N=360) are randomly assigned to one of four experimental conditions. All participants, smokers of e10 cigarettes per day, receive 12 weeks of combined pharmacological treatment (varenicline) and group psychological intervention. During the 40 week extended treatment period, participants will receive either: (1) 40 weeks of varenicline availability + Relapse Prevention Treatment (Relapse Prevention + varenicline); (2) 40 weeks of Relapse Prevention Treatment (Relapse Prevention); (3) 40 weeks of Extended Nonspecific Treatment [based on a Health Education model (Extended Nonspecific) ]; and (4) No further treatment (Brief Treatment). Participants will be assessed at baseline on smoking behavior, nicotine dependence, depression diagnosis, alcohol problems, demographics, mood disturbance, treatment support, stress, health status, motivation for change, and licit and illicit drug use. At weeks 12, 24, 52, 64, and 104, participants will be assessed on self-reported smoking verified by carbon monoxide and cotinine assays, as well as on psychometric measures. The primary hypotheses, which posit differences between conditions, will be evaluated by GEE using intent to treat analysis. We will also test a series of secondary hypotheses that evaluate a series of moderating and mediating variables to determine more precisely how treatment is related to abstinence. If this research is successful, it will provide a treatment that produce abstinence rates considerably higher than those obtained from those currently available.